Key aspects of the synaptic homeostasis hypothesis of sleep function will be tested in the first 3 projects of this center application, including that: i) brain plasticity during wakefulness leads to molecular, electrophysiological and metabolic "traces" reflecting the occurrence of synaptic potentiation; ii) synaptic potentiation, in turn, is responsible for higher levels of slow waves during subsequent sleep; and iii) sleep slow waves are necessary for the renormalization of cortical circuits after learning and for the enhancement of performance after sleep. This project will test the synaptic homeostasis hypothesis in a clinical population[unreadable]subjects with major depressive disorder. About half of depressives show an acute antidepressant response to sleep deprivation. Many of the same molecular markers of synaptic potentiation that are induced by sleep deprivation are also induced by antidepressant drugs, suggesting that sleep deprivation and antidepressants both act by the induction of plasticity-related genes. According to the hypothesis, activation of such genes should be associated with increased sleep slow waves. Aim 1 of this study will confirm that depressives can be subdivided into those who show a normal decline of slow wave activity (SWA) across the night and those who do not, and extend our preliminary findings that depressives can also be subdivided into those who show normal vs. abnormal topography and local homeostatic regulation of SWA. Aim 2 will employ the same visuomotor task as Projects II and III to demonstrate that the subgroup of depressives with abnormal SWA homeostasis will show impaired local homeostasis and decreased sleep-dependent learning in comparison to the subgroup with more normal SWA homeostasis. Finally, Aim 3 will test the hypothesis' prediction that sleep deprivation will produce an antidepressant response only in depressed subjects with a normal time course and topography of SWA during the night, as well a normal SWA activity response to the homeostatic challenge of sleep deprivation.